Protein phosphatase 2A (PP2A) functions as a multimetric enzyme that contains the catalytic C subunit, a scaffolding A-subunit and one of a large array of regulatory B-subunits. Eukaryotic cells contain over 200 biochemical distinct PP2A complexes derived from differential combinations of A, B, C and other subunits. The regulatory subunits are expressed in a tissue-specific manner, leading to the presence of different PP2A complexes in different mammalian tissues (Virshup and Shenolikar, 2009). Moreover, it is these regulators, rather than the catalytic subunit that provide the substrate specificity and to catalyze distinct dephosphorylation events to impose different functional outcomes.
Although a tumor suppressor role of PP2A has been shown in a variety of immortalized human cell types (Chen et al., 2004; Eichhorn et al., 2009; Janssens and Goris, 2001; Rangarajan et al., 2004; Sablina et al., 2007; Zhao et al., 2003), the genetic and/or the epigenetic evidence pointing to a prevalent inactivation of PP2A in human malignancy have not been reported. Somatic mutations in the A subunit of the PP2A complex, which can result in the loss of B subunit binding (Ruediger et al., 2001), were found only in up to 15% of some human cancers (Calin et al., 2000; Ruediger et al., 2001; Takagi et al., 2000; Tamaki et al., 2004; Wang et al., 1998; Westermarck and Hahn, 2008), and the reduced expression of PP2A subunit B56γ3 has been reported only in some cancer cell lines (Chen et al., 2004; Zhao et al., 2003). In general, the genetic or epigenetic changes of PP2A complexes in human cancer remains to be defined, as is its impact on cancer signaling or therapeutic responses to targeted therapy.
One of the PP2A regulated cancer signaling pathways is the mTOR pathway, a key component of PI3K pathway that many cancer cells are addicted to for growth advantage (Guertin and Sabatini, 2007; Sabatini, 2006). Although small molecule mTORC1 inhibitors, such as rapamycin and its analogues have shown promising rationals for their use in cancer therapy and have been approved for clinical application (Guertin and Sabatini, 2007; Hudes et al., 2007), these inhibitors have had only limited successes and the clinical outcome is unpredictable. While a known mechanism of rapamycin resistance is linked to its feedback activation of AKT phosphorylation through PI3K and mTORC2 (O'Reilly et al., 2006; Sarbaisov et al., 2006), further understanding the resistance mechanism and identifying the biomarkers that help to predict the therapeutic response have become important topics (Mao et al., 2008; Scott et al., 2009; Thomas et al., 2006).